title: CB1 cannabinoid receptors couple to focal adhesion kinase to control insulin release.
abstract: Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1 cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability. However, the molecular cascade coupling agonist-induced cannabinoid receptor activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endocannabinoids (anandamide and 2-arachidonoylglycerol) or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for second-phase insulin release. Inhibition of endocannabinoid synthesis or FAK activity precluded insulin release. We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes.
authors.affiliation: From the Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland,; the Department of Medical Biochemistry and Biophysics, Division of Molecular Neurobiology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Malenczyk
authors.affiliation: From the Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jazurek
authors.affiliation: the Department of Medical Biochemistry and Biophysics, Division of Molecular Neurobiology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Keimpema
authors.affiliation: the Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli, Naples, Italy.
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Silvestri
authors.affiliation: From the Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Janikiewicz
authors.affiliation: the Department of Psychological and Brain Sciences, Gill Center for Neuroscience, Indiana University, Bloomington, Indiana 47405.
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.affiliation: the Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, I-80078 Pozzuoli, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: From the Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Redowicz
authors.affiliation: the Department of Medical Biochemistry and Biophysics, Division of Molecular Neurobiology, Karolinska Institutet, SE-17177 Stockholm, Sweden,; the School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom. Electronic address: Tibor.Harkany@ki.se.
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.affiliation: From the Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland,. Electronic address: a.dobrzyn@nencki.gov.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dobrzyn
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063388:Endocannabinoids / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005089:Exocytosis; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D005989:Glycerides / Q000494:pharmacology; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D022142:Secretory Vesicles / Q000235:genetics / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D005989:Glycerides; D007328:Insulin; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C078814:anandamide
keywords: Cannabinoid Receptors; Cytoskeleton; Endocannabinoids; Exocytosis; Focal Adhesion Kinase; Insulin Release